11alpha-hydrocarbylsulfonyloxy-3,5-pregnadienes



Ila-HYDROCARBYLSULFONYLOXY-Sfl- PREGNADIENES George R. Allen, Jr.,v Paramus, N.J., William S. Allen,

Pearl River, N.Y., and Martin J. Weiss, Oradell, N.J., assignors to American Cyauamid Company, New York, N.Y., a corporation of Maine No Drawing. Filed July 9, 1958, Ser. No. 747,328

6 Claims. (Cl. 260-397.45)

This invention relates to new steroid compounds. More ore in which R is a lower alkanoyl radical, R is hydrogen or a lower alkanoyloxy radical, X 1s:a halogen atom and C9-C11 is the trivalent radical C =OH-; CH-CH--O S Oz-lOWer alkyl or I Y I oHc H--0s oh -1 radical The compounds of the present invention can be prepared, for example, from steroids such as 21-acetoxy- 16ot,17ot oxido 1la-p-t0luenesulfonyloxy-4 pregnene-3, 20-doine; 21 acetoxy-l1a-methanesulfonyloxy-16a,17o;- oxido-4-pregnene-3,ZO-dione and the like described and claimed in the copending application Serial No. 686,868, filed September 30, 1957, now abandoned. They can also be prepared from analogous progesterone derivatives such as l6cc,l7a-oxido-4,9(ll)-pregnadiene- 3,20-dione and 1IZX-IHElhHIICSUIfOHYIOXY-l60L,170L-OXldO-4- pregnene-3,20-dione described in United States Patent No. 2,703,799.

The various oxido derivatives, on treatment with hydrogen halide, can be converted to the corresponding 17ahydroxy-16fi-halo compounds which, on reaction with an organic acid anhydride in the presence of a strong acid catalyst, e.g. p-toluenesulfonic acid, will give the compounds of this invention.

Treatment of these latter compounds with reagents such as sodium acetate in hot glacial acetic acid will result in the reformation of the corresponding A -3-one steroids and the development of the important 16a-alkanoyloxy-l7a hydroxy steroids. The resulting compounds which are disclosed in United States Patent 2,831,002 and in co-pending application Serial No. 720,564, filed March 11, 1958, can be converted into the highly active compounds disclosed and claimed in copending applications Serial No. 747,331, filed July 9, 1958, now abandoned, Serial No. 720,564, filed March 11, 1958, and in United States Patent 2,789,118, one of which is a com v 3,006,933 Patented Oct. 31,1961

mercial product sold under the name Aristocort (brand of triamcinolone). (A -pregnadiene-9a-fluoro-11,8,16a, l7d,2l-tetrol-3,20-dione).

The following examples describe the preparation of the compounds of the present invention in greater detail.

Example 1 A solution of 2l-acetoxy-l6u,17m-oxido-1loop-toluenesulfonyloxy-4-pregnene-3,20-dione (5.0 g.) in acetic acid (100 ml.) is treated with hydrobromic acid (3032%) in acetic acid (5.0 ml.) at 15, and the mixture is allowed .to warm to room temperature over a period of thirty minutes. Water is then slowly added until precipitation is complete, and the crystalline precipitate is filtered and air dried. This material is redissolved in acetic acid (100 ml.) and recrystallized with the aid of water. This gives 21 acetoxy 16;8-bromo17ot-hydroxy-1la-p-toluenesulfonyloxy-4-pregnene-3,20-dione, melting point 112-114. A portion of this is recrystallized from acetone-water to give material melting at 135 (dec.); ultraviolet spectrum:

' mg? 229 mu (6 24,300) g A solution of 21-acetoxy-16fi-bromo-17ot-hydroxy-11ap-toluenesulfonyloxy-4-pregnene-3,20-dione (4.0 g.) in acetic anhydride (35 m1.) is treated with p-toluenesulfonic acid monohydrate (1.34 g.) and is allowed to stand overnight at roomtemperature. The solution is then chilled to 5 C. and 35 ml. of water is added. After stirring for about one hour, more water is added, until the precipitation is complete. The product is filtered, washed well with water and dried. This gives 3,17a ,21-triacetoxy-16flbromo 11a p-toluenesulfonyloxy-3,S-pregnadiene-ZO- one, melting point 134 C. (dec.). Recrystallization from acetone-water raises the melting point to 152 C. (dec.); ultraviolet spectrum:

AER 227 mu (e 30,000)

Example 2 A solution of Zl-acetoxy-l6a,l7a-oxido-4,9(lll)-pregnadiene-3,20-dione in acetic acid is treated with hydrobromic acid (30-32%) in a manner similar to that described in- Example 1. The product, 2l-acetoxy-16/3- bromo 17a hydroxy 4,9(l1)-pregnadiene-3,20-dione, after recrystallization from acetone-petroleum ether melts at 148 (dec.); ultraviolet spectrum:

In a further experiment following the procedure of Example 1, 21-acetoxy-11a-p-toluenesul fonyloxy-16a, l7a-oxido-4-preg'nene-3,20 dione is treated with sodium iodide in acetic acid and the mixture worked up in a similar manner. The extract is evaporated to dryness to give 2l-acetoxy-l7ot-hydroxy-l6B-iodo-lla-p-toluenesulfonyloxy-4-pregnene-3,ZO-dione; ultraviolet spectrum:

X3552 229 in (6 29,000)

In a manner similar to that described in Example 1, 21 acetoxy 17a hydroxy-16B-iodo-1lot-p-toluenesulfonyloxy-4-pregnene-3,ZO-dione in acetic anhydride is treated with p-toluenesulfonic acid monohydrate. After the usual workup, the product 3,17u,21-triacetoxy-16piodo 11a-p-toluenesul-fonyl0xy-3,S-pregnadiene-ZO-one is isolated, washed with water and dried; ultraviolet spectrum: ALQQ 227 mu (6 29,200)

Example '4 In a manner similar to that described in Example 7, 21 acetoxy 1lot-methanesulfonyloxy-l6a,17a-oxido-4- A suspension of l6fl-bromo-17a-hydroxy-1lot-methanesulfonyloxy-4-pregnene-3,ZO-dione in methylene chlopregnene-3,20-dione is treated with hydrobromic acid is isolated and dried; ultraviolet spectrum? Example I In a manner similar to that described in Example 1, 16a,17a-oxido-4,9 l 1)-pregnadiene-3,20-dione is treated cracked ice.

ride is treatedtwith ptolue nesulfonic acid hydrate and acetic anhydride. The mixture is magnetically stirred during eighteen hours; all solid dissolves during this time. The methylene chloride is removed at 40 0., and the residual solution is magnetically stirred with excess water while being chilled in an ice bath. After the acetic anhydride has hydrolyzed, the solution is diluted with water and extracted with methylene chloride. The solvent is removed to give 3,17u-diacetoxy-l6B-bromo-1lot-methanesulfonyloxy-3,S-pregnadiene-ZO-one as an amorphous material; ultraviolet spectrum:

as? 235 i (6 18,500) I Example 8' A solution of 16a,17a-epoxy-1la-methanesulfonyloxy- 4-pregnene-3,20-dione in carbon tetrachloride-acetic acid (1:1 v./v.) is cooled to 18 C..f This solution is treated with a solution prepared by saturating glacial acetic acid with'hydrogen chloride at C. The solution is magnetically stirred for thirty minutes and then poured onto The solid which separates is collected by filtration to give l6fi-chloro-l7a-hydroxy-llot-methanewith hydrobromic acid (-32%) in acetic acid. After the usual workup, 16B bromo-l7u-hydroxy-4,9(1l)-pregnadiene-3,2-0-dione is washed, dried and recrystallized from acetone-petroleum ether; melting point .182l84;

. ultraviolet spectrum:

REES 238 11,. 617,000 In a manner similar to that described in Example 1, 16,8 bromo 4 170a hydroxy-4,9(1l)-pregnadiene-3,Z0

'dione in 25 ml. of-acetic anhydride is treated with ptoluenesulfonic acid monohydrate. After the usual workup, the product is recrystallized from dilute acetone to give 3,17 diacetoxy-16,8-bromo-3,5,9( l 1 )-pregnatriene- 20-one as white needles, melting point 94-98" C.; ultraviolet spectrum:

tim 236 m,. (e 19,700)

Example 6 In the manner described inExample 1, l6u, 1.7cz-OXid0- '4,9(11)-pregnadiene-3,20-dione is treated with sodium iodide in acetic acid, and the mixture is workedup in a sulfonyloxy-4-pregnene-3,20-dione; ultraviolet spectrum:

A suspension of l 6p-chloro-17ot-hydroxy-1lwmethane sulfonyloxy-4-pregnene-3,20-dione in excess acetic anhydride containing p-toluenesulfonic acid is magnetically stirred at room.- temperature for seventeen hours. The solution is poured into excess water, chilled in an ice bath and magnetically stirred until the acetic anhydride similar manner to give 17a-hydroxy-16fi-iodo-4,9(11

pregnadiene-3,20-dione as white needles melting at 166- 168 C. (dec.); ultraviolet spectrum:

33:3 238 m 0s 17,300) .[ocl +118f (methanol). In the manner described in Example 1, l7o -hydroxyl6fl-iodo-4,9(l1)-pregnadiene-3,20-dione is allowed to react with p-toluenesulfonic acid and acetic anhydride, The product, 3,17mdi-acetoxy-l6fi-iodo3,5,9 (,1 l ),.-pregna.-

triene-ZO-one, is obtained as white needles, melting point tion; an oily layer separates. The mixture is stirred m-agnetically for thirtyminutes and then poured onto 1000 ml. of cracked ice. The solid which separates is collected by filtration and dried to give l6B bromo17u-hydroxyc methanesulfonyloxy-4-pregnene-3,20-dione; melting point -168 (dec.); ultraviolet spectrum:

atfi assm -ge 17,600)

is hydrolyzed. The solid is collected by filtration and dried under reduced pressure over phosphorus pentoxide to give 3,l7a-diacetoxy-l6/9-chloro-1la-methanesulfonyloxy-3,S-pregnadiene-ZO-one; ultraviolet spectrum: 7\ 235 my (6 19,000).

i Example 9 A solution of 1Gfl-bromo-17a-hydroxy-4,9(1l)-pregnadiene-3,20-dione and p-toluenesulfonic acid in 25 ml. of butyric anhydride is treated as described in Example 8. The resulting product 3,l7a-di-n-butyryloxy-16fi bromo-3,5 ,9 l 1 -pregnatriene-20-one has 213 235 my. (6 20,000) Example 10 A solution of 3,17a,21-triacetoxy-1loz-p-toluenesulfonyloxy-l6 3-bromo-3,5-pregnadiene-20-one (1.0 g.) and sodium acetate (2.0 g.) in acetic acid (18 ml.) is refluxed for nineteen and one-half hours Water is then added, and the mixture is extracted with methylene chloride. The extract is washed twice with water, once with saturated sodium bicarbonate solution, once more with water and dried over magnesiumsulfa-te. The extract is evaporated to dryness, and the resultant hard glass dissolved in benzene and chromatographed on silica gel (30 g.). The product, 16a,2l-diacetoxy-17a-hydroxy-4,9 1 1) -pregnadiene 3,20-di0ne, is eluted with benzene-ether (1:1) and crystallized from acetone-petroleum ether to give CI'YS? tals, melting point l20-122 C. (bubbles), resolidifying and re-melting at 184-186" C.; ultraviolet spectrum:

x1553 7239 my. (6 14,200)

'Ihe infrared spectrum is identical to that of an authentic sample. a

- Example 11 methylene chloride, and the organic solution is washed with saturated sodium bicarbonate solution and water. The organic solution is taken to dryness, and the residue is crystallized from acetone-petroleum ether to give crystals; melting point 184-187 C.; ultraviolet spectrum:

A523 238 mp. (6 16,500)

The infrared spectrum of this material and that of an authentic sample of 16a,21-diacetoxy-17u-hydroxy-4, 9( 11)-pregnadiene-3,20-dione are identical.

Example 12 In a manner similar to that described in Example 10,

3,17a,21 triacetoxy-llot-ptoluenesulfonyloxy-l6fl-iodo- 3,5-pregnadiene-20-one in acetic acid is refluxed with sodium acetate. After the usual Workup, the residue is crystallized from acetone-petroleum ether to give the product 16a,21-diacetoxy-17a-hydroxy-4,9 1 1 )-pregnadiene-3,20-dione. The infrared spectrum is identical to that of an authentic sample.

Examwle 13 In a manner similar to that described in Example 10, 3,17a,21 trihydroxy-16p-bromo-l la-methanesulfonyloxy- 3,5-pregnadiene-20-one is refluxed With acetic acid containing sodium acetate. After the usual workup, the product, 16a,21-diacetoxyl7a-hydroxy-4,9 1l)-pregnadiene-3,20-dione, is crystallized from acetone-petroleum ether. The infrared spectrum is identical to that of an authentic sample.

Example 14 A mixture of 3.300 g. (6.72 moles) of l6u-bromo-3,5, 9( l1)-pregnatriene-3,l7a-diol-20-one 3,17-diacetate, 6.60 g. of anhydrous sodium acetate and 100 ml. of glacial acetic acid is allowed to reflux during six hours. All solid dissolves when the reflux temperature is reached. The cooled solution is concentrated to near dryness; the residue is triturated with 200 ml. of water. The solid is collected by filtration to give 2.489 g. of solid, melting point l35-160 C. This solid is dissolved in 15 ml. of benzene and chromatographed on a silica gel column x 100 mm). The column is washed with 200 ml. of methylene chloride-benzene (30: 500 ml. of methylene chloride, 200 ml. of chloroform-methylene chloride (20:80), 400 m1. of chloroform-methylene chloride (50:50); these washings are discarded. The column is then washed with 1400 ml. of chloroform; 100 ml. percolates are collected, and the material eluted in percolates 8-12 is combined. Recrystallization from methylene chloride-petroleum ether gives 1.446 g. (57% yield) of 4,9(11)-pregnadiene-l6u,17a-diol-3,20-dione 16-acetate as white feathery needles, melting point l70 -l80 (bubbling); ultraviolet spectrum:

glacial acetic acid are heated six hours to give 1.307 g. (37% yield) of needles, melting point 170-180 C. (bubbling) after recrystallization from methylene chloride petroleum ether. The infrared spectrum of this material was identical with that of an authentic sample of 16a acetoxy 17a hydroxy-4,9(11)-p-regnadiene-3,20- dione.

Example 16 The material from Example 7 is heated with sodium acetate in refluxing glacial acetic acid as described previously. This procedure gives white needles, meltmg point 6 173-188 C. (bubbling), after chromatography and recrystallization from benzene-petroleum ether. The infrared spectra of this material and that of an authentic sample of l6a-acetoxy-17a-hydroxy-4,9(1 l)-pregnadiene- 3,20-dione are identical.

Example 17 A mixture of 1.650 g. of 3,17a-diacetoxy-16fi-chloro- 11a-methanesulfonyloxy-B,S-pregnadiene-ZO-one, 6.60 g. of anhydrous sodium acetate and 50 ml. of glacial acetic acid is allowed to reflux during six hours. The cooled solution is concentrated to near dryness; the residue is triturated with ml. of water. The solid thus obtained is chromatographed on silica gel. That material eluted with chloroform is recrystallized from acetone-petroleum ether 7 to give 16u-acetoxy-17a-hydroxy-4,9(I'D-pregnadiene-3,20-dione as white crystals, melting point 179- 188 C. (bubbling). The infrared spectrum is identical to that of an authentic sample.

Example 18 A solution of 0.384 g. (1.0 mole) of 1-6a-acetoxy-17ahydroxy-4,9(11)-pregnadiene-3,20-dione, 15 ml. of methanol, 5 ml. of water and 0.17 ml. of 37% hydrochloric acid solution is allowed to reflux during three hours. The solution is concentrtaed until solid begins crystallizing, chilled, in an ice bath and filtered to give 0.231 g. (67% yield) of crystals, melting point -196 C. Two recrystallizations from acetone-petroleum ether give white prisms, melting point 220223 C.; ultraviolet spectrum:

AXQQ 239 mu (6 17,200)

oi: B13020-.. [X

in which R is a lower alkanoyl radical, R is a member of the group consisting of hydrogen and lower alkanoyloxy radicals, X is a (B) halogen atom and R is a member of the group consisting of lower alkyl and mononuclear aryl radicals.

References Cited in the file of this patent UNITED STATES PATENTS 2,703,799 Bergstrom Mar. 8, 1955 2,835,667 Ercoli et al. May 20, 1958 2,859,224 Farrar et a1. Nov. 4, 1958 OTHER REFERENCES Rosenkranz et al.: Fortschritte der Chemie organischer Naturstofie (Vienna, -3), vol. 10, pages 291-93. 

1. THE COMPOUND 3,17A,21-TRIACETOXY-16B-BROMO-11AP-TOLUENESULFONYLOXY-3,5-PREGNADIENE-20 -ONE. 